Synthetic tools for new antibiotics

描述（由申请人提供）：复杂的天然产品仍然是开发新型治疗方法的灵感和创新的重要来源之一。然而，它们的复杂性在生成生物测试所需的类似物或数量时提出了合成挑战。一个结构基序，创造了一个特殊的挑战是含有季立体中心的碳环结构的对映选择性合成。在本提案中，描述了合成化学工具，其将允许具有两个季立体中心、邻位季-叔立体中心和邻接的季-叔-季立体中心的碳环结构的有效的、对映选择性的构建。合成工具将在一个有价值的新方向上扩展最近开发的Birch-Cope序列。此外，该项目描述了一种策略，将这些工具应用于对映选择性合成胡芦巴烯D，一种具有抗菌性能的二萜天然产物。开发胡芦巴烯D的合成方法和产生具有抗生素特性的其他复杂分子的工具将有助于解决抗生素耐药性不断升级的危机。 公共卫生相关性：复杂的天然产物仍然是开发新型治疗方法，特别是抗生素治疗的灵感和创新的重要来源之一。胡芦巴烯D是近年来发现的一种二萜类天然产物，具有独特的化学结构和抗菌活性，是天然产物化学中发现的丰富化合物的代表。拟议的项目将开发合成化学工具，以允许高效和特异性地合成胡芦巴烯D，从而促进其作为一种新的抗生素治疗的发展。随着现代医学面临抗生素耐药性危机的迅速发展，这里开发的工具有可能促进在寻求改善治疗方法方面的重要进展。

DESCRIPTION (provided by applicant): Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments. However, their complexity presents synthetic challenges when generating analogs or quantities necessary for biological testing. One structural motif that creates a particular challenge is the enantioselective synthesis of carbocyclic structures containing quaternary stereocenters. In the current proposal, synthetic chemistry tools are described which will allow the efficient, enantioselective construction of carbocyclic structures with two quaternary stereocenters, vicinal quaternary- tertiary stereocenters and contiguous quaternary-tertiary-quaternary stereocenters. The synthetic tools will extend the recently developed Birch-Cope sequence in a valuable, new direction. Furthermore, the project describes a strategy to apply these tools to the enantioselective synthesis of trigonochinene D, a diterpene natural product with antimicrobial properties. The development of a synthesis of trigonochinene D and the tools to generate other complex molecules with antibiotic properties will assist in addressing the escalating crisis of antibiotic resistance. PUBLIC HEALTH RELEVANCE: Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments, especially antibiotic therapy. Trigonochinene D is a recently reported diterpene natural product which, with its unique chemical architecture and antibiotic activity, is representative of the riches found in natural product chemistry. The proposed project will develop synthetic chemistry tools to permit the efficient and specific synthesis of trigonochinene D, thereby facilitating its development as a new antibiotic treatment. With modern medicine facing a burgeoning crisis in antibiotic resistance, the tools developed here have the potential to facilitate important advances in the search for improved therapeutic treatments.